Intramolecular carbenoid insertions: The reactions of α-diazoketones derived from pyrrolyl and indolyl carboxylic acids with rhodium(II) acetate

Article abstract of DOI:10.1016/S0040-4020(00)00725-0

α-Diazoketones derived from pyrrolyl- and indolyl-carboxylic acids were prepared and their Rh₂(OAc)₄ catalyzed decomposition chemistry was studied. These reactions generally resulted in the alkylation of the heteroaromatic system by the ketocarbenoid and in some instances the systems underwent CH or NH insertions. Evidence that some of these reactions proceed via a cyclopropane intermediate is presented. The methodology described provides facile access to fused pyrrolyl- or indolyl-cycloalkanone systems wherein the carbonyl is beta to the heteroaromatic system. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00725-0

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 8063±8069
Intramolecular Carbenoid Insertions: the Reactions of
a-Diazoketones Derived from Pyrrolyl and Indolyl Carboxylic
Acids with Rhodium(II) Acetate
*
Mohamed Salim and Alfredo Capretta
Institute of Molecular Catalysis, Department of Chemistry, Brock University, St. Catharines, Ontario, Canada L2S 3A1.
Received 14 July 2000; accepted 15 August 2000
AbstractÐa-Diazoketones derived from pyrrolyl- and indolyl-carboxylic acids were prepared and their Rh2(OAc)4 catalyzed decompo-
sition chemistry was studied. These reactions generally resulted in the alkylation of the heteroaromatic system by the ketocarbenoid and in
some instances the systems underwent CH or NH insertions. Evidence that some of these reactions proceed via a cyclopropane intermediate
is presented. The methodology described provides facile access to fused pyrrolyl± or indolyl±cycloalkanone systems wherein the carbonyl is
beta to the heteroaromatic system. q 2000 Elsevier Science Ltd. All rights reserved.
Insertions of a-ketocarbenoids into pyrrolyl and indolyl
systems have been reported previously by a number of
groups.1 The chemical outcome of these reactions is depen-
dant on several factors but especially the nature of the
substituent on the nitrogen and the catalyst employed. For
example, reactions of pyrroles and N-alkyl pyrroles with
metal-stabilized carbenoids derived from a-diazocarbonyl
compounds generally result in alkylation products.2
However, the introduction of an electron withdrawing
group (an acyl moiety, for example) onto the nitrogen of
the heterocycle allows for the isolation of cyclopropane
containing products.3 The nature of the carbenoid structure
can also have a dramatic effect.4 Davies, for example, has
used the metal-catalyzed decomposition of vinyldiazo-
methanes in the presence of pyrroles for a tandem cyclopro-
panation/Cope rearrangement and entry to the tropane
system.5 Intramolecular reactions of a-ketocarbenoids
tethered at the nitrogen of a pyrrole or indole fragment
have also been reported previously by Galeazzi,6 Jefford7
and MuÈller.8
moieties has shown that atypical chemistry can be induced if
the carbenoid and the aromatic system are separated by a
single methylene tether.9 A natural extension of this work
involves the investigation of the analogous nitrogenous
heterocyclic systems and we have prepared and studied
the chemistry of a-diazoketones derived from pyrrolyl-
and indolyl-carboxylic acids. The systems prepared herein
differ from those studied by others in that the catalyst used is
rhodium(II) acetate exclusively and in that the tethered
a-diazoketone is linked at either the C2 or C3 position of
the heteroaromatic rather than at the nitrogen.
Preparation of the desired a-diazoketones containing
pyrrole moieties, 1-diazo-3-(3-pyrrolyl)-2-propanone (2a,
Scheme 1) and 1-diazo-3-(2-pyrrolyl)-2-propanone (2b),
could not be achieved using the standard protocol wherein
the precursor carboxylic acid, 2-(3-pyrrolyl)acetic acid (1a)
or 2-(2-pyrrolyl)acetic acid (1b), is treated with either
sulphonyl chloride or oxalyl chloride to generate the
acid chloride and then reacted with diazomethane.
Under these conditions, derivitization takes place at
the pyrrole. However, use of a carbodiimide coupling
agent,10 such as DDC (1,3-dicyclohexylcarbodiimide) or
Our work involving the intramolecular insertion of carbe-
noids into furanyl, benzofuranyl, thienyl and benzothienyl
Scheme 1.
Keywords: carbenoids; pyrrole; indole; cyclopropanation.
* Corresponding author. Tel.: 11-905-688-5550 ext. 3848; fax:11-905-688-2789; e-mail: fcaprett@chemiris.labs.brocku.ca
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00725-0

8064
M. Salim, A. Capretta / Tetrahedron 56 (2000) 8063±8069
Scheme 2.
Scheme 3.
EDC
(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide),
followed by 1,2-H migration rather than a concerted, single
step.
prevented any undesired side reactions and allowed for
the preparation of the required a-diazoketones in good
yield. Decomposition of 2a in dichloromethane using
rhodium(II) acetate gave 4,6-dihydrocyclopenta[b]pyrrol-
5(1H)-one (3, in 85% yield) while decomposition of the
isomeric diazoketone 2b under the same conditions gave
the bicyclic 3 (in 24% yield) and 1H-pyrrolizin-2(3H)-one
(4, in 65% yield).
1-Diazo-3-(2-indolyl)-2-propanone (5, Scheme 2) behaved
much like its pyrrole analog (2b) with Rh2(OAc)4 catalyzed
decomposition leading to an alkylation product (3,4-di-
hydrocyclopenta[b]indol-2(3H)-one, 6) and an NH insertion
product (1H-pyrrolo[1,2-a]indol-2(3H)-one, 7). In a similar
fashion, decomposition of 1-diazo-3-(3-indolyl)-2-propa-
none 8 (Scheme 3) allowed for the production of 6.
However, when the transformation of 8!6 was followed
via NMR spectroscopy, an intermediate cyclopropane 9
could be clearly seen. Proton assignments were made by
preparing a series of indolyl diazoketones (10, 13 and 15)
and carrying out their Rh2(OAc)4 induced decomposition.
Spectra of cyclopropanes 11, 14, and 16 were collected and
compared with those of 9 thereby securing its structure. It is
worth pointing out that this outcome is in marked contrast to
the previously reported work on the a-diazoketone derived
from 3-indoleacetic acid which, upon treatment with
BF3´Et2O, allowed for the preparation of 1,2,3,4-tetra-
hydro-cyclopent[b]indol-2-one via a proposed spirocyclic
intermediate.11
Mechanistically, one can rationalize the alkylation products,
3 for example, as having arisen from either a zwitterionic or
cyclopropane intermediate. A zwitterionic route would have
the electrophilic carbenoid attacking the pyrrole to give a
dipolar intermediate which could rearomatize to give the
alkylation product 3. The second possibility involves the
addition of the carbenoid across a p-bond of the pyrrole
to give a cyclopropane intermediate which then unravels
and rearomatizes to give 3. The matter may be further
complicated, however. If the cyclopropane is formed in a
stepwise fashion, the cyclopropane pathway merges into the
dipolar mechanism. An extension of the arguments used to
explain intermolecular reactions of carbenoids and pyrroles
would seem to favor the mechanism involving the zwitter-
ionic intermediates.1 In addition, the production of 4 marks
the ®rst example of an apparent insertion into a pyrrole N±H
bond and is likely the result of nitrogen ylide formation
The existence of a cyclopropane intermediate in the indole
series came, initially, as very much of a surprise since a
zwitterionic intermediate in this series should be stabilized
Figure 1.

M. Salim, A. Capretta / Tetrahedron 56 (2000) 8063±8069
8065
Scheme 4.
to a greater extent over that of the analogous pyrrole system
due to delocalization of charge through the fused benzo
moiety and onto the nitrogen (Fig. 1). In light of the forma-
tion 9 in the transformation of 8!6, this is, clearly, not the
case. It may be argued that the resonance contributor with
the intact aromatic system (I) is favored over those wherein
the aromaticity is disrupted (II and III). With the positive
charged more localized on the benzylic carbon shown in I,
the reaction pathway is diverted to the more energetically
stable cyclopropane and then onto the alkylation product
isolated.
electron donating substituents on the resultant Rh2(OAc)4
catalyzed decomposition chemistry.
Experimental
Starting materials were purchased from Aldrich Chemical
Co. and used without further puri®cation. 1H- and 13C NMR
spectra were recorded on a Bruker Avance DPX-300 Digital
FT spectrometer (at 300.13 and 75.03 MHz, respectively)
with chloroform-d as the solvent and internal reference
unless otherwise noted. Low resolution mass spectra (MS)
and high resolution mass spectra (HRMS) were obtained on
Concept 1S double focusing mass spectrometer interfaced
to a Kratos DART acquisition system and a SUN Spectro-
station 10 workstation using XMACH3 software. Ions were
generated using electron impact (EI). Silica gel used for
column chromatography (5.0% of 100 mesh up; 47.6% of
100±200 mesh and 47.4% of 200 mesh down) was
purchased from Aldrich Chemical Co. Silica gel 60 F254
(E. Merck Co.) plates of 0.2 mm thickness were used for
analytical thin layer chromatography (TLC).
The effect of a longer methylene tether between the indole
and the diazoketone was also investigated in order to deter-
mine the scope of the chemistry (Scheme 4). Reaction of
the commercially available indole-3-propionic acid with
thionyl chloride followed by addition to an ethereal solution
of diazomethane resulted in the formation of 1-diazo-4(-3-
indole)-2-butanone 18 in 70% yield. When this diazoketone
was treated with rhodium(II) acetate, 1,3,4,9-tetrahydro-2H-
carbazol-2-one (19) was the sole product isolated in 75%
yield. Interestingly, no 1H NMR evidence for an
intermediate cyclopropane was obtained.
Rh2(OAc)4 catalyzed decomposition of 1-diazo-(3-
pyrroyl)-2-propanone (2a). Pyrrole-3-acetic acid14 (1a)
(0.50 g, 4.0 mmol) was dissolved in dry dichloromethane
(30 mL) and treated with 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (0.84 g, 4.4 mmol).
Stirring under argon was continued for two hours at which
time the reaction mixture was added to a cooled (ice bath),
ethereal solution of diazomethane (14 mmol). The solution
was stirred for two hours during which time a black pre-
cipitate formed. The solution was ®ltered and the ®ltrate was
concentrated under reduced pressure. The product was puri-
®ed by column chromatography using silica gel and ethyl
acetate/hexane (1:3) as the eluent to afford 1-diazo-(3-
pyrroyl)-2-propanone (2a) (0.27 g, 1.8 mmol, 45% yield).
The product showed: Rfˆ0.44 (ethyl acetate/hexane, 1:1);
1H NMR (CDCl3, 300 MHz): d 3.53 (2H, s, CH2), 5.26 (1H,
s, CHN2), 6.14 (1H, m, ArH), 6.71 (1H, s, ArH), 6.78 (1H,
m, ArH), 8.20 (1H, br, N±H); 13C NMR (CDCl3, 75 MHz):
d 39.7 (CH2), 54.1 (CHN2), 109.1, 115.8, 116.9, 118.5,
195.1 (CO).
Diazoketone 2012 was prepared from the commercially
available indole-3-butyric acid and treatment with
Rh2(OAc)4 in dichloromethane resulted in the formation
of two products inseparable via column chromatography:
6,8,9,10-tetrahydrocyclohepta[b]indol-7(5H)-one (21) and
the CH insertion product 3-(1H-indol-3-yl)cyclopentanone
(22). Structural assignments were achieved through careful
study of the mixture via 13C NMR. It should be noted that
the production of 22 was not unexpected as there is a great
deal of precedence for the formation of ®ve membered rings
via intramolecular C±H insertions.13
The chemistry described above has not only provided an
increased understanding of the mechanism involved in the
intramolecular insertion of carbenoids into pyrroles and
indoles but has also allowed for the development of a facile
synthetic route to an interesting class of heterocycle. The
methodology provides access to fused pyrrolyl- or indolyl±
cycloalkanone systems wherein the carbonyl is beta to the
heteroaromatic system (in contrast to a Friedel±Crafts
acylation which would place the carbonyl in the alpha
position). Work is currently being directed towards the
preparation of a series of analogous a-diazoketones contain-
ing various substituents on the pyrrole or indole nitrogen in
an effort to examine the effect of electron withdrawing or
To a solution of 1-diazo-(3-pyorryl)-2-propanone (2a)
(0.10 g, 0.67 mmol) in dichloromethane (35 mL) was
added
a
catalytic amount of rhodium(II) acetate
(,10 mg). The solution was stirred under argon at room
temperature for four hours. The solvent was removed by

8066
M. Salim, A. Capretta / Tetrahedron 56 (2000) 8063±8069
evaporation under reduced pressure and the residue was
puri®ed by column chromatography using silica gel and
ethyl acetate/hexane (1:1) as the eluent. The product
4,6-dihydrocyclopenta[b]pyrrol-5(1H)-one (3) (0.068 g,
0.57 mmol, 85% yield) showed: Rfˆ0.26 (ethyl acetate/
stirred for another hour and the solvent removed under a
reduced pressure to give a solid residue. The dicyclohexyl-
urea (DCU) was removed by crystallization from ether, and
the supernatant puri®ed by column chromatography using
silica gel and ethyl acetate/hexane (1:2) as eluent. The
product 1-diazo-3-(2-indolyl)-2-propanone (5) (0.056 g,
0.28 mmol, 50% yield) showed: Rfˆ0.23 (ethyl acetate/
1
hexane, 1:4); H NMR (CDCl3, 300 MHz): d 3.34 (2H, s,
CH2), 3.38 (2H, s, CH2), 6.26 (1H, s, ArH), 6.77 (1H, s, ArH),
8.32 (1H, br, N±H); 13C NMR (CDCl3, 75 MHz): d 39.5
(CH2), 40.7 (CH2), 104.8, 119.7, 129.4, 216.5 (CO); MS
(m/z [RI%]): 121 [M]1 (50), 93 [M2CO]1 (100); HRMS:
For C7H7NO calculated 121.0528, observed 121.0533.
1
hexane, 1:2); H NMR (CDCl3, 300 MHz): d 3.37 (2H, s,
CH2), 5.28 (1H, br, CHN2), 6.32 (1H, s, ArH), 7.11 (2H, m,
ArH), 7.31 (1H, d, Jˆ8 Hz, ArH), 7.54 (1H, d, Jˆ8 Hz,
ArH), 8.72 (1H, br, NH); 13C NMR (CDCl3, 75 MHz): d
40.5 (CH2), 55.6 (CHN2), 102.5, 111.3, 120.3, 120.5, 122.3,
128.7, 131.8, 136.9, 192.1 (CO); MS [EI]1 (m/z [RI%]): 199
[M]1 (7), 171 [M2N2]1 (31), 143 [M2N2±CO]1 (52), 130
[M2COCHN2]1 (27); HRMS: For C11H9N3O calculated
199.0746, observed 199.0753.
Rh2(OAc)4 catalyzed decomposition of 1-diazo(2-pyrro-
lyl)-2-propanone (2b). Pyrrole-2-acetic acid2 (2a) (0.50 g,
4.0 mmol) and 1,3-dicyclohexylcarbodiimide (DCC)
(0.89 g, 4.3 mmol) were dissolved in dichloromethane
(60 mL) and the reaction mixture was stirred under argon
at room temperature for one hour. The solution was slowly
added to stirred, cooled (ice bath) solution of ethereal diazo-
methane (12 mmol) and, after 3 h, the solvent was removed
by evaporation under reduced pressure. The dicyclohexyl-
urea (DCU) was removed from the residue by crystallization
several times from ether. The reaction mixture was then
puri®ed by column chromatography using silica gel and
ethyl acetate/hexane (1:2) as the eluent. The product (2b)
was isolated as yellow crystals (0.48 g, 3.2 mmol, 80%
yield) and showed: Rfˆ0.27 (ethyl acetate/hexane, 1:2);
1H NMR (CDCl3, 300 MHz): d 3.59 (2H, s, CH2), 5.25
(1H, s, CHN2), 5.99 (1H, s, ArH), 6.12 (1H, m, ArH),
6.72 (1H, m, ArH), 8.71 (1H, br, N±H); 13C NMR
(CDCl3, 75 MHz): d 40.0 (CH2), 55.2 (CHN2), 108.1,
108.9, 118.6, 124.5, 193.1 (CO); MS (m/z [RI%]): 149
[M]1 (40), 121 [M2N2]1 (12), 93 [M2N2±CO]1 (34), 80
[M2COCHN2]1 (100); HRMS: For C7H7N3O calculated
149.0589, observed 149.0593.
To a stirred solution of 1-diazo-3-(2-indolyl)-2-propanone
(5) (50 mg, 0.25 mmol) in dry dichloromethane (20 mL), a
catalytic amount of rhodium(II) acetate (,5 mg) was added.
The reaction mixture was stirred under argon at room
temperature for 2 h. The solvent was evaporated, and the
residue was puri®ed by column chromatography using silica
gel and ethyl acetate: hexane (1:2) as eluent to give
3,4-dihydrocyclopenta[b]indol-2(3H)-one (6) and 1H-
pyrrolo[1,2-a]indol-2(3H)-one (7) (NH insertion product),
in 25 and 70% yield, respectively. The product 6 showed:
Rfˆ0.42 (ethyl acetate/hexane, 1:2); 1H NMR (CDCl3,
300 MHz): d 3.54 (2H, s, CH2), 3.57 (2H, s, CH2), 7.20
(2H, m, ArH), 7.42 (1H, d, ArH), 7.51 (1H, d, ArH), 8.12
(1H, br, N±H); 13C NMR (CDCl3, 75 MHz): d 39.8 (CH2),
39.8 (CH2), 112.0, 114.2, 119.4, 120.8, 122.5, 124.8, 136.4,
138.8, 214.6 (CO); MS [EI]1 (m/z [RI%]): 171[M]1 (48),
143 [M2CO]1 (100), 115 [M2C2H4CO] (15); HRMS: For
C11H9NO calculated 171.0684, observed 171.0695. The
1
product 7 showed: Rfˆ0.68 (ethyl acetate/hexane, 1:2); H
To a stirred solution of 1-diazo(2-pyrrolyl)-2-propanone
(2b) (0.26 g, 1.7 mmol) in dry dichloromethane (40 mL), a
catalytic amount of rhodium(II) acetate (,10 mg) was
added. The reaction mixture was stirred under argon at
room temperature for 2 h. The solvent was removed by
evaporation under a reduced pressure and the products
were puri®ed by column chromatography using silica gel
and ethyl acetate/hexane (1:4) as the eluent. Two products
were collected: 4,6-dihydrocyclopenta[b]pyrrol-5(1H)-one
(3) (0.05 g, 0.41 mmol, 24% yield) and 1H-pyrrolizin-
2(3H)-one (4) (0.13 g, 1.1 mmol, 65% yield). Product 4
showed: Rfˆ0.57 (ethyl acetate/hexane, 1:4); 1H NMR
(CDCl3, 300 MHz): d 3.55 (2H, s, CH2), 4.41 (2H, s,
CH2), 6.03 (1H, d, ArH), 6.29 (1H, m, ArH), 6.78 (1H, d,
ArH); 13C NMR (CDCl3, 75 MHz): d 37.9 (CH2), 54.8
(CH2), 102.2, 111.6, 115.9, 130.5, 210.1 (CO); MS (m/z
[RI%]): 121 [M]1 (50), 93 [M2CO]1 (100); HRMS: For
C7H7NO calculated 121.0528, observed 121.0534.
NMR (CDCl3, 300 MHz): d 3.75 (2H, s, CH2), 4.51 (2H, s,
NCH2), 6.40 (1H, s, ArH), 7.20 (2H, m, ArH), 7.28 (1H, d,
ArH), 7.64 (1H, d, ArH); 13C NMR (CDCl3, 75 MHz): d
38.0 (CH2), 52.7 (CH2), 96.2, 110.1, 120.8, 121.3, 122.0,
130.9, 134.0, 136.9, 209.0 (CO); MS [EI]1 (m/z [RI%]):
171[M]1 (70), 143 [M2CO]1 (100), 115 [M2C2H4CO]1
(31); HRMS: For C11H9NO calculated 171.0684, observed
171.0689.
Rh2(OAc)4 catalyzed decomposition of 1-diazo-3-(3-
indoly)-3-propanone (8). A solution of indole-3-acetic
acid (0.40 g, 2.3 mmol) in a dry tetrahydrofuran (30 mL)
was cooled to 08C (ice bath) and stirred under argon. Two
drops of dry dimethylformamide were added to the ¯ask.
Thionyl chloride (0.3 g, 2.5 mmol) was slowly added and
the reaction mixture stirred for another two hours. The
solvent was removed under reduced pressure, and re-
dissolved in dry dichloromethane. The acid chloride was
slowly added to a cooled, ethereal solution of diazomethane
and the reaction mixture was stirred for two hours. The
product was puri®ed by chromatography on silica gel
using ethyl acetate/hexane (1:2) as the eluent to give
1-diazo-3-(3-indoly)-3-propanone (8) (0.40 g, 1.9 mmol,
83% yield). The compound showed: Rfˆ0.44 (ethyl ace-
tate/hexane, 1:1); 1H NMR (CDCl3, 300 MHz): d 3.79
(2H, s, CH2), 5.21 (1H, s, CHN2), 7.11 (1H, s, ArH), 7.22
(2H, m, ArH), 7.30(1H, d,, ArH), 7.90 (1H, d, ArH), 8.36
Rh2(OAc)4 catalyzed decomposition of 1-diazo-3-(2-
indolyl)-2-propanone (5). To a solution of indole-2-acetic
acid15 (0.1 g, 0.57 mmol) dissolved in dry dichloromethane
(35 mL) was added dicyclohexylcarbodiimide (DCC)
(0.13 g, 0.63 mmol). The reaction mixture was stirred
under an argon atmosphere for one hour. The resulting solu-
tion was added slowly to a cooled (ice bath) solution of
ethereal diazomethane (20 mL). The reaction mixture was

M. Salim, A. Capretta / Tetrahedron 56 (2000) 8063±8069
8067
(1H, br, N±H); 13C NMR (CDCl3, 75 MHz): d 38.4 (CH2),
54.7 (CHN2), 109.4, 111.8, 119.1, 120.4, 122.9, 123.9,
127.5, 136.7, 194.7 (CO); MS [EI]1 (m/z [RI%]): 199
[M]1 (14), 171 [M2N2]1 (83), 143 [M2N2±CO]1 (83),
130 [M2COCHN2]1 (100), 115 [M2CH2COCHN2]1
(28); HRMS: For C11H9N3O calculated 199.0746, observed
199.0754.
dichloromethane as the eluent. Compound 12 (0.16 g,
0.89 mmol, 95% yield) showed: Rfˆ0.73 (ethyl acetate/hex-
ane, 1:1); 1H NMR (CDCl3, 300 MHz): d 3.51 (2H, s, CH2),
3.56 (2H, s, CH2), 3.73 (3H, s, CH3), 7.18 (1H, t, ArH),
7.27(1H, t, ArH), 7.34 (1H, d, ArH), 7.50 (1H,d, ArH);
13C NMR (CDCl3, 75 MHz): d 31.7 (CH2), 38.7 (CH2),
40.4 (CH3), 110.0, 111.9, 119.3, 120.2, 121.8, 124.8,
139.4, 139.5, 214.3 (CO); MS [EI]1 (m/z [RI%]): 185
[M]1 (75%), 157 [M2CO]1 (100%), 142 [M2COCH3]1
(13%), 128 [M2CH2CO±CH3]1 (4%); HRMS: For
C12H11NO calculated 185.0841, observed 185.0843.
To a stirred solution of 1-diazo-3-(3-indoly)-3-propanone
(8) (0.15 g, 0.75 mmol) in dry dichloromethane (40 mL), a
catalytic amount of rhodium(II) acetate (,10 mg) was
added. The reaction mixture was stirred under argon at
room temperature for 2 h. The solvent was evaporated,
and the residue was puri®ed by column chromatography
using silica gel and ethyl acetate/hexane (1:2) as the eluent
to give 3,4-dihydrocyclopenta[b]indol-2(3H)-one (6)
(126 mg, 0.74 mmol, 95% yield). Intermediate cyclo-
propane (9) was observed when a solution of 1-diazo-3-
(3-indolyl)-3-propanone (8) (,5 mg) in CDCl3 was treated
with a catalytic amount of rhodium(II) acetate and the reac-
tion monitored by 1H NMR. Intermediate 9 (which appeared
after approximately 5 min and was completely converted to
6 over the next 60 min) showed: 1H NMR (CDCl3,
300 MHz): d 2.55 (1H, dd, Jˆ16, 3 Hz), 2.85 (1H, dd,
Jˆ16, 3 Hz), 4.41 (1H, br t), 5.23 (1H, br) and 6.70±7.60
(Ar-H).
Intermediate cyclopropane (11) was observed when a
solution of 1-diazo-3-(1-methyl-3-indolyl)-2-propanone
(,5 mg) in CDCl3 was treated with a catalytic amount of
rhodium(II) acetate and the reaction monitored by 1H NMR
(a spectrum taken every 5 min). Intermediate 11 (which
appeared after approximately 5 min and was completely
1
converted to 12 over the next 60 min) showed: H NMR
(CDCl3, 300 MHz): d 2.64 (1H, dd, Jˆ16, 4 Hz), 2.99
(1H, dd, Jˆ16, 4 Hz), 3.32 (3H, CH3), 4.41 (1H, br t),
7.02±7.49 (Ar).
Rh2(OAc)4 catalyzed decomposition of 1-diazo-3-(2-
methyl indolyl)-2-propanone (13). 2-Methyl indole-3-
acetic acid (0.2 g, 1.0 mmol) was dissolved in dry tetra-
hydrofuran (25 mL), cooled to 08C and stirred under an
atmosphere of argon. Oxalyl chloride (0.15 g, 1.2 mmol)
was added slowly followed by two drops of DMF. The
reaction mixture was stirred at room temperature for one
hour. The solvent was evaporated under a reduced pressure,
dry benzene (10 mL) was added and subsequently evapo-
rated under a reduced pressure. The residue was re-
dissolved in dry tetrahydrofuran (15 mL) and was added
dropwise to a cooled (ice bath) solution of diazomethane
in ether (25 mL). The reaction mixture was stirred for
another hour, ®ltered, and the solvent evaporated under a
reduced pressure. The residue was puri®ed by column
chromatography using silica gel and ethyl acetate/hexane
(1:2) as the eluent, to give 13 (0.16 g, 0.75 mmol, 75%
yield). The compound showed: Rfˆ0.27 (ethyl acetate/
Rh2(OAc)4 catalyzed decomposition of 1-diazo-3-(3-[1-
methyl indolyl])-2-propanone (10). 1-Methyl indole-3-
acetic acid16 (0.30 g, 1.6 mmol) was dissolved in dry
dichloromethane (25 mL) and the solution was stirred
under argon. Oxalyl chloride (0.24 g, 1.9 mmol) was
added slowly followed by two drops of DMF and the
reaction mixture stirred at room temperature for one hour.
The solvent was evaporated under a reduced pressure. Dry
benzene (10 mL) was added and subsequently evaporated
under a reduced pressure. The residue was redissolved in
dry dichloromethane (15 mL) and added dropwise to an
ethereal solution of diazomethane (35 mL) at 08C. The reac-
tion mixture was stirred for another two hours at which time
the solution was ®ltered and the solvent evaporated under a
reduced pressure. The residue was puri®ed by column
chromatography using silica gel and ethylacetate/hexane
(1:2) as the eluent to give the desired product (10) (0.29 g,
1.36 mmol, 85% yield) which showed: Rfˆ0.48 (ethyl
1
hexane, 1:2); H NMR (CDCl3, 300 MHz): d 2.36 (3H, s,
CH3), 3.73 (2H, s, CH2), 5.13 (1H, s, CHN2), 7.18 (2H, m,
ArH), 7.28 (1H, d, ArH), 7.48 (1H, d, ArH), 8.51 (1H, s,
NH); 13C NMR (CDCl3, 75 MHz): d 12.1 (CH3), 37.4
(CH2), 54.3 (CHN2), 105.3, 110.9, 118.2, 120.3, 122.0,
128.8, 133.5, 135.7, 194.9 (CO); MS [EI]1 (m/z [RI%]):
213 [M]1 (20),185 [M2N2]1 (59), 144 [M2COCHN2]1
(100); HRMS: For C12H11N3O calculated 213.0902,
observed 213.0909.
1
acetate/hexane, 1:1); H NMR (CDCl3, 300 MHz): d 3.77
(2H, s, CH2), 3.80 (3H, s, CH3), (1H, s, CHN2), 7.01 (1H, s,
NCH), 7.20 (1H, t, ArH), 7.27 (1H, d, ArH), 7.34 (1H, t,
ArH), 7.58 (1H, d, ArH); 13C NMR (CDCl3, 75 MHz): d
33.2 (CH3), 38.3 (CH2), 54.5 (CHN2), 107.9, 109.9, 119.2,
119.9, 122.5, 128.0, 128.5, 137.5, 194.6 (CO); MS [EI]1
(m/z [RI%]): 213 [M]1 (34%),185 [M2N2]1 (25%), 157
[M2CON2]1 (22%), 144 [M2COCHN2]1 (100%); HRMS:
For C12H11N3O calculated 213.0902, observed 213.0911.
1-Diazo-3(3-[2-methyl indolyl])-2-propanone (13) (0.12 g,
0.56 mmol) was dissolved in dry dichloromethane (40 mL)
and treated with a catalytic amount of rhodium(II) acetate
(,10 mg). The reaction mixture was stirred for three hours
under argon at room temperature. The solvent was evapo-
rated under a reduced pressure and the residue puri®ed using
silica gel column chromatography with ethyl acetate/hexane
(1:3) as the eluent. Cyclopropane 14 (0.067 g, 0.36 mmol,
65% yield) showed: Rfˆ0.29 (ethyl acetate/hexane, 1:1); 1H
NMR (CDCl3, 300 MHz): d 1.52 (3H, s, CH3), 2.65 (1H, d,
Jˆ15 Hz, one of CH2), 2.78 (1H, d, Jˆ15 Hz, one of CH2),
4.38 (1H, br, N±H), 6.04 (1H, s, CH), 6.85 (1H, d, Jˆ8 Hz,
To a solution of rhodium(II) acetate (,20 mg) in dichloro-
methane (40 mL) was added a solution of 1-diazo-3-(1-
methyl-3-indole)-2-propanone (0.2 g, 0.94 mmol) in
dichloromethane via a syringe pump. The reaction was
allowed to stir under an argon atmosphere at room tempera-
ture for an additional 30 min at which time the solvent was
evaporated under a reduced pressure. The residue was puri-
®ed by ®ltration through a short pad of silica gel using

8068
M. Salim, A. Capretta / Tetrahedron 56 (2000) 8063±8069
ArH), 6.91 (1H, t, Jˆ7 Hz, ArH), 7.35 (1H, t, Jˆ8 Hz,
ArH), 7.53 (1H, d, Jˆ7 Hz, ArH); 13C NMR (CDCl3,
75 MHz): d 29.7 (CH3), 52.4 (CH2), 71.7 (CH), 112.7,
116.9, 120.2, 120.4, 125.8, 133.9, 154.9, 182.4, 206.7
(CO); MS [EI]1 (m/z [RI%]): 185 [M]1 (79), 170
[M2CH3]1 (100), 157 [M2CO]1 (31), 144 [M2CO±
CH]1 (10), 115 [M2CH3±CH2COCH]1 (20); HRMS: For
C12H11NO calculated 185.0841, observed 185.0841.
acetate and the reaction monitored by 1H NMR (a spectrum
taken every 10 min). Intermediate 16 (which appeared after
approximately 5 min and was completely converted to 17
over the next 60 min) showed: 1H NMR (CDCl3, 300 MHz):
d1.80 (3H, CH3), 2.59 (1H, dd, Jˆ16, 3 Hz), 3.00 (1H, dd,
Jˆ16, 3 Hz), 4.45 (1H, br t), 6.95±7.60 (Ar).
Rh2(OAc)4 catalyzed decomposition of 1-diazo-4(3-indo-
lyl)-2-butanone (18). Indole-3-propionic acid (0.30 g,
1.5 mmol) was dissolved in dry tetrahydrofuran (30 mL)
and stirred under an argon atmosphere at 08C. Dimethyl-
formamide (two drops) were added to the reaction ¯ask
followed by thionyl chloride (0.22 g, 1.9 mmol). The reac-
tion mixture was stirred for two hours at 08C at which time
the solvent was removed by evaporation under a reduced
pressure. The residue was redissolved in dry tetrahydrofuran
and immediately added slowly to a stirred ethereal solution
of diazomethane (50 mL, ,5 mmol) at 08C. The reaction
mixture was stirred for two hours, ®ltered and the solvent
evaporated to dryness under a reduced pressure. The product
was puri®ed by column chromatography on silica gel using
ethyl acetate/hexane (1:2) as the eluent to give 1-diazo-4(-3-
indolyl)-2 butanone (18) (0.23 g, 1.1 mmol, 70% yield). The
Rh2(OAc)4 catalyzed decomposition of 2-diazo-4-(3-
indolyl)-3-butanone (15). To a solution of indole-3-acetic
acid (0.30 g, 1.7 mmol) dissolved in dry tetrahydrofuran
(35 mL) and stirred under argon at 08C, was added thionyl
chloride (0.22 g, 1.8 mmol) and two drops of dry dimethyl-
formamide. Twenty minutes following the addition, the
color of the reaction mixture changed to brown. Stirring
was continued for another two hours. The solvent was
removed by evaporation under a reduced pressure and the
residue redissolved in a dry tetrahydrofuran (20 mL). The
solution was added dropwise to a stirred solution of ethereal
diazoethane (roughly three equivalents) at 08C. The reaction
mixture was stirred for another two hours at which time a
few drops of acetic acid were added to destroy the excess of
the diazoethane. The reaction mixture was ®ltered and
evaporated to dryness under a reduced pressure. The product
was puri®ed by chromatography on silica gel using ethyl
acetate/hexane (1:2) as the eluent. The product (15) was
isolated in 65% yield (0.24 g, 1.1 mmol) and showed:
Rfˆ0.28 (ethyl acetate/hexane, 1:2); 1H NMR (CDCl3,
300 MHz): d 1.9 (3H, s, CH3CN2), 3.91 (2H, s, CH2),
6.99 (1H, s, ArH), 7.15 (2H, m, ArH), 7.31 (1H, d, ArH),
7.61 (1H, d, ArH), 8.28 (1H, br, N±H); 13C NMR (CDCl3,
75 MHz): d 8.4 (CH3), 35.6 (CH2), 62.4 (CN2), 108.3,
111.2, 118.4, 118.8, 119.7, 122.2, 123.2, 127.0, 136.1,
192.4 (CO); MS (m/z [(RI%)]: 213 [M]1 (3), 185
[M2N2]1 (56), 170 [M2N2±CH3]1 (6), 157
[M2CH2CN2]1 (27), 130 [M2COCN2(CH3)]1 (100);
HRMS: For C12H11N3O calculated 213.0902, observed
213.0903.
1
product showed: Rfˆ0.48 (ethyl acetate/hexane, 1:1); H
NMR (CDCl3, 300 MHz): d 2.69 (2H, t, Jˆ7 Hz, CH2),
3.10 (2H, t, Jˆ7 Hz, CH2), 5.12 (1H, s, CHN2), 6.91 (1H,
s, ArH), 7.17 (2H, m, ArH), 7.32 (1H, d, ArH), 7.58 (1H, d,
ArH), 8.36 (1H, br, N±H); 13C NMR (CDCl3, 75 MHz): d
20.5(CH2), 41.1 (CH2), 54.5 (CHN2), 111.2, 114.3, 118.4,
119.0, 121.7, 121.7, 126.9, 136.2, 195.1 (CO); MS (m/z
[RI%]): 213 [M]1 (5), 185 [M2N2]1 (37), 156 [M2N2±
CO]1 (29), 143 [M2COCHN2]1 (27), 130 [M2
CH2COCHN2]1 (100), 115 [M2CH2CH2COCHN2]1 (9);
HRMS: For C12H11N3O calculated 213.0902, observed
213.0898.
1-Diazo-4(-3-indolyl)-2-butanone (18) (0.10 g, 0.47 mmol)
was dissolved in dry dichloromethane (30 mL) under an
argon atmosphere and treated with rhodium(II) acetate
(,10 mg). The reaction mixture was stirred at room
temperature for three hours at which time the solvent was
removed by evaporation under a reduced pressure. The
product was puri®ed by chromatography on silica gel
using ethyl acetate/hexane (1:2) as the eluent. 1,3,4,9-Tetra-
hydro-2H-carbazol-2-one (19) was isolated in 75% yield
(65 mg, 0.35 mmol). The product showed: Rfˆ0.48 (ethyl
2-Diazo-4-(3-indolyl)-3-butanone (15) (0.10 g, 0.47 mmol)
was dissolved in dry dichloromethane (20 mL) and treated
with a catalytic amount of rhodium(II) acetate (,10 mg).
The reaction mixture was stirred for three hours under argon
at room temperature. The solvent was evaporated under a
reduced pressure and the residue puri®ed using silica gel
column chromatography with dichloromethane as the
eluent. The yield of the isolated product (17) was 90%
(78 mg, 0.42 mmol) which showed: Rfˆ0.54 (dichloro-
1
acetate/hexane, 1:1); H NMR (CDCl3, 300 MHz): d 2.76
(2H, t, Jˆ7 Hz, CH2), 3.08 (2H, t, Jˆ7 Hz, CH2), 3.61 (2H,
s, CH2), 7.15 (2H, m, ArH), 7.30 (1H, d, ArH), 7.49 (1H, d,
ArH), 7.86 (1H, br, N±H); 13C NMR (CDCl3, 75 MHz): d
20.2 (CH2), 38.8 (CH2), 39.9 (CH2), 109.9, 111.3, 118.5,
120.2, 122.4, 127.0, 130.5, 137.0, 208.8 (CO); MS [EI]1
(m/z [RI%]): 185 [M]1 (93), 156 [M2CO]1 (38), 143
[M2CH2CO]1 (100), 130 [M2C2H4CO]1 (14), 115
[M2C3H6CO]1 (11); HRMS: For C12H11NO calculated
185.0841, observed 185.0842.
1
methane); H NMR (CDCl3, 300 MHz): d 1.46 (3H, d,
Jˆ7 Hz, CH3), 3.54±3.62 (3H, m, CH1CH2), 7.20 (2H,
m, ArH), 7.42 (1H, d, Jˆ8 Hz, ArH), 7.53 (1H, d,
Jˆ8 Hz, ArH), 8.14 (1H, br, N±H); 13C NMR (CDCl3,
75 MHz): d 15.9 (CH3), 38.9 (CH2), 44.3 (CH2), 112.1,
112.3, 119.5, 120.8, 122.5, 124.8, 138.8, 142.1, 217.6
(CO); MS (m/z [RI%]): 185 [M]1 (56), 157 [M2CO]1
(100), 130 [M2C3H3O]1 (47), 115 [M2C4H6O]1 (5);
HRMS: For C12H11NO calculated 185.0841, observed
185.0850.
Rh2(OAc)4 catalyzed decomposition of 1-diazo-5-(3-
indolyl)-2-pentanone (18). A solution of indole-3-butyric
acid (0.4 g, 1.96 mmol) and two drops of dry dimethyl-
formamide in dry tetrahydrofuran (50 mL) were cooled
(ice bath) and stirred under an argon atmosphere. Thionyl
chloride (280 mg, 2.36 mmol) was added and the reaction
Intermediate cyclopropane (16) was observed when a solu-
tion of 2-diazo-4-(3-indolyl)-3-butanone (15) (,5 mg) in
CDCl3 was treated with a catalytic amount of rhodium(II)

M. Salim, A. Capretta / Tetrahedron 56 (2000) 8063±8069
8069
6. Galeazzi, E.; Guzman, A.; Pinedo, A.; Saldana, A.; Torre, D.;
Muchowski, J. M.; Can J. Chem. 1983, 61, 454.
mixture was stirred for one hour. The solution was slowly
transferred to a cooled, ethereal solution of diazomethane
(50 mL, 6 mmol) and allowed to react for two hours. The
solvent was removed by evaporation under a reduced
pressure and the resultant residue was puri®ed by column
chromatography on silica gel using ethyl acetate/hexane
(1:2) as the eluent. The product, 1-diazo-5-(3-indolyl)-2-
pentanone (18) (0.29 g, 1.3 mmol, 65% yield) was a isolated
as a yellow solid and showed: Rfˆ0.51 (ethyl acetate/
7. Jefford, C. W.; Johncock, W. Helv. Chim. Acta 1983, 66, 2666;
Jefford, C. W.; Zaslona, A. Tetrahedron. Lett. 1985, 26, 6035;
Jefford, C. W.; Kubota, T.; Zaslona, A. Helv. Chim. Acta 1986,
69, 2048.
8. MuÈller, P.; Polleux, P. Helv. Chim. Acta 1998, 81, 317.
9. Frampton, C. S.; Pole, D. L.; Yong, K.; Capretta, A. Tetra-
hedron Lett. 1997, 38, 5081; Yong, K.; Salim, M.; Capretta, A.
J. Org. Chem. 1998, 63, 9828.
1
hexane, 1:1); H NMR (CDCl3, 300 MHz): d 1.96 (2H, m,
CH2), 2.32 (2H, br t, CH2), 2.73 (2H, t, CH2), 6.92 (1H, s,
ArH), 7.08 (2H, m, ArH), 7.30 (1H, d, ArH), 7.52 (1H, d,
ArH), 8.71 (1H, br, N±H); 13C NMR (CDCl3, 75 MHz): d
24.9 (CH2), 26.0 (CH2), 40.9 (CH2), 54.8 (CHN2), 111.8,
115.5, 119.1, 119.3, 122.1, 122.3, 127.8, 136.8, 195.8 (CO);
MS [m/z (RI%)]: 227 [M]1 (6), 199 [M2N2]1 (19), 170
[M2N2HCO]1 (25), 156 [M2COCH2N2]1 (8), 143
[M2C3H4N2O]1 (100), 130 [M2C2H4COCHN2]1 (74),
115 [M2C5H7N2O]1 (13); HRMS: For C13H13N3O
calculated 227.1059, observed 227.1073.
10. Holt, D. H. G.; Wall, D. K. J. Chem. Soc. (C) 1970, 971.
11. Franceshetti, L.; Garzon-Arurbeh, A.; Mohmoud, M. R.;
Natalini, B.; Pellicciari, R. Tetrahedron Lett. 1993, 34, 3185.
12. Preparation of the diazoketone was achieved using the
standard conditions wherein carboxylic acid is ®rst converted to
the acid chloride which is then treated with ethereal diazomethane.
Curiously, if the acid chloride was concentrated prior to addition to
diazomethane, 2,3,4,9-tetrahydrocarbazol-1-one was formed in
95% yield. Its structure was unambiguously determined by NMR
(1H NMR (CDCl3, 300 MHz): d 2.24 (2H, m, CH2), 2.68 (2H, t,
Jˆ6 Hz, CH2), 2.98 (2H, t, Jˆ6 Hz, CH2), 7.13 (1H, m, ArH), 7.36
(1H, m, ArH), 7.49 (1H, d, Jˆ8 Hz, ArH), 7.64 (1H, d, Jˆ8 Hz,
ArH), 9.96 (1H, br, N±H); 13C NMR (CDCl3, 75 MHz): d 21.29,
(CH2), 24.89 (CH2), 38.17 (CH2), 112.75, 120.13, 121.15, 125.64,
126.86, 129.62, 131.12, 138.16, 191.70 (CO)); MS (m/z (RI%) 185
[M]1 (100), 156 [M2CO]1 (25), 143 [M2CH2CO]1 (24), 129
[M2C2H4CO]1 (72), 115 [M2C4H6O]1 (5); HRMS: For
C12H11NO calculated 185.08406, observed 185.08385) and X-ray
crystallography (see Fig. 2). Crystals were monoclinic having a
1-Diazo-5-(3-indolyl)-2-pentanone (18) (0.10 g, 0.44
mmol) was dissolved in dry dichloromethane (20 mL)
under an argon atmosphere and treated with rhodium(II)
acetate (,10 mg). The reaction was stirred at room
temperature for three hours at which time the solvent was
removed by evaporation under a reduced pressure. Chroma-
tography of the reaction products on silica gel (using ethyl
acetate/hexane 1:1) yield 21 and 22 as an inseparable
mixture in 78% yield. The products showed an Rfˆ0.34
(ethyl acetate/hexane, 1:1). Compound (21) showed 13C
NMR (CDCl3, 75 MHz): 22.5, 25.0, 43.2, 44.1, 111.0,
112.1, 119.5, 119.9, 122.4, 122.8, 127.0, 137.1, 207.4.
Compound (22) showed 13C NMR (CDCl3, 75 MHz):
30.3, 34.2, 38.6, 45.7, 111.8, 118.4, 119.0, 120.0, 120.4,
125.4, 129.3, 135.8, 220.0. Tentative assignments were
made based on the intensities of the signals and by a
comparison of the observed chemical shifts with those of
similar compounds.
Ê
Ê
space group of P2(1)/n, aˆ10.247(3) A, bˆ5.8100(18) A, cˆ
Ê
Ê 3
15.877(3) A, bˆ97.49(3)8, Vˆ937.2(4) A , and Zˆ4; the ®nal R
factor was 0.0546 for 8897 measured re¯ections). This Friedel±
Crafts chemistry can be avoided if the acid chloride in added
directly to the diazomethane without prior concentration. Using
this procedure, puri®cation by using column chromatography on
silica gel gave the desired 1-diazo-5(-3-indole)-2-pentanone in
65% yield along with small amounts of the methyl ester of the
starting acid and 2,3,4,9-tetrahydrocarbazol-1-one.
Acknowledgements
The authors wish to thank Brock University and the Natural
Sciences and Engineering Research Council of Canada for
their ®nancial support, Mr Tim Jones (Brock University) for
mass spectral analysis and Dr Christopher S. Frampton
(Roche Products, UK) for X-ray crystallography.
References
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Figure 2. ORTEP of 2,3,4,9-tetrahydrocarbazol-1-one.
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